Useful pro-drug forms of theophylline

Abstract

There is provided novel and useful pro-drug forms of theophylline having the formula: ##SPC1## Wherein R represents a member selected from the group consisting of a straight or branched C 4 -C 20 alkyl group, a straight or branched C 4 -C 20 alkenyl group, a substituted phenyl group of a substituted or unsubstituted naphthyl group whose substituents are selected from the group consisting of a hydroxy group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 acyloxy group, and a halogen atom (Cl, Br, I), and a substituted or unsubstituted heteroaromatic group whose substituents are selected from the group consisting of a hydroxy group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 acyloxy group, and a halogen atom (Cl, Br, I), and wherein A represents a member selected from the group consisting of a --CO-- group, a --CO--(CH 2 ) n --CO-- group, wherein n represents an integer of from 1 to 16, a --CO--CH=CH--CO-- group (cis or trans), a ##SPC2## Group, and a ##SPC3## Group. The compounds of this invention are useful in the treatment of asthma in warm-blooded animals. Upon administration, the compounds of this invention slowly go into solution and subsequently cleave prior to and/or during the absorption process, releasing theophylline in a sustained manner at a non-toxic, therapeutic level; that is, without the large blood level variations normally observed when theophylline per se is administered.

What we claim is: 
     
       1. A pro-drug of theophylline having the formula ##SPC7## wherein R represents a member selected from the group consisting of straight or branched C 4  -C 20  alkyl, straight or branched C 4  -C 20  alkenyl, substituted phenyl or substituted or unsubstituted naphthyl whose substituents are selected from the group consisting of hydroxy, C 1  -C 4  alkyl, C 1  -C 4  alkoxy, acyloxy derived from an alkanoic acid of up to 4 carbon atoms chlorine, bromine, and iodine, and 2-,3-,4-pyridyl or quinoline and wherein A represents a member selected from the group consisting of --CO--, --CO--(CH 2 ) n  --CO-- wherein n represents an integer of from 1 to 16, --CO--CH=CH-- CO-(cis or trans), ##SPC8##   and ##SPC9##   
     
     
       2. The compound of claim 1 wherein R represents an odd numbered alkyl of from C-7 to C-20. 
     
     
       3. The compound of claim 1 wherein R represents oleyl. 
     
     
       4. The compound of claim 1 wherein R represents phenyl substituted in the 4-position with hydroxy or C 1  -C 4  alkoxy, 2-hydroxyphenyl, or 2-acyloxyphenyl wherein the acyloxy is derived from an alkanoic acid of up to 4 carbon atoms. 
     
     
       5. The compound of claim 1 wherein A represents --CO--(CH 2 ) n  --CO-- in which n is an integer of from 1-4. 
     
     
       6. The compound of claim 1 wherein A represents trans --CO--CH=CH--CO--. 
     
     
       7. The compound of claim 1: 7-hexanoyltheophylline. 
     
     
       8. The compound of claim 1: 7-octanoyltheophylline. 
     
     
       9. The compound of claim 1: 7-decanoyltheophylline. 
     
     
       10. The compound of claim 1: 7-dodecanoyltheophylline. 
     
     
       11. The compound of claim 1: 7-myristyltheophylline. 
     
     
       12. The compound of claim 1: 7-palmityltheophylline. 
     
     
       13. The compound of claim 1: 7-stearyltheophylline. 
     
     
       14. The compound of claim 1: 7-[2-hydroxy]-benzoyltheophylline. 
     
     
       15. The compound of claim 1: 7-[2-acetyloxy]-benzoyltheophylline. 
     
     
       16. The compound of claim 1: 7,7'-carbonylditheophylline. 
     
     
       17. The compound of claim 1: 7,7'-succinylditheophylline. 
     
     
       18. . The compound of claim 1: 7,7'-terephthaloylditheophylline. 
     
     
       19. The compound of claim 1: 7,7'-fumaroylditheophylline. 
     
     
       20. The compound of claim 1: 7,7'-glutarylditheophylline. 
     
     
       21. The compound of claim 1: 7,7'-adipyldilheophylline.